Genomic pathology for genomic biology

Tremendous advances in our understanding of the mammalian genome have led to new enthusiasm for molecular-based medicine. Indeed, genomic biology is now the driving force in health sciences and medical research, and meetings are convened to discuss the topic of “Genomic Medicine”. New Institutes and Centers have proliferated to take advantage of the technology. But, in their euphoria, have the new “genomic biologists” forgotten pathology, the study of disease? Or, has pathology forgotten them? More cynically, do molecular biologists truly believe that their technology can replace the pathologist with machines? In their ignorance, their technology is underserved.

Is this “disconnect” based on arrogance or ignorance? The ignorance is evident in the current enthusiasm for creating more mutant mice. The animal houses in Universities are already overflowing with mice ¹ . Now, a new international consortium is intent on knocking out the entire mouse genome, thus creating, gene by gene, thousands of new mutant mouse strains. This program is certain to establish the experimental mouse resources that can potentially form the basis for understanding the genetic and molecular biology of disease. Enthusiastic planners, in some countries, indicate that they are prepared to study the diseases in these mice. The question is whether pathology is prepared for Genomic Biology ²? Genome-based biology, founded initially on the mouse and eventually on humans, will require comparative pathologists who can recognize the gross and microscopic patterns of disease in both species and who can integrate the disease patterns with the genomic changes ². In the past, comparative pathologists have served as the gatekeepers of disease models, validating the similarity to, or divergence from, human diseases. Now they will be asked to recognize the sometimes subtle histopathological variations related to minor changes in the genome. Historically, the ancients recognized no difference between healing animals or man and most “healers” treated both ³. Later, interested observers frequently used animals for experimental observation of anatomy, physiology and pathology. When unable to dissect human cadavers, they resorted to animals, leading to numerous erroneous assumptions about human anatomy. Two examples are the bicornuate uterus of the cow and the spiral intestine of the pig, both of which are frequently found in medieval depictions of human anatomy. In fact, it has been said that veterinary medicine was based on observation and facts during eras when human medicine was based on theory and incantations. With high economic and sometimes spiritual value, animals were the leading resource for the study of biology and pathology.

Modern comparative pathology originated with Rudolph Virchow, the “Founder of Modern Pathology”, who stated that “there is little difference” between diseases in animals and in man ². The theme was taken up by William Osler, the “Founder of Modern Medicine”, who started a Veterinary College at McGill and is given credit for coining the term “one medicine”. Interestingly, Osler is also considered by many as the “Founder of Veterinary Pathology”. Sadly, we lost the enthusiasm exhibited by our predecessors.

Regrettably, the disciplines of medical and veterinary pathology have drifted apart, leaving the field of comparative pathology to a dedicated few. As documented elsewhere, neither group of pathologists is training protégées for the modern form of comparative pathology, Genomic Pathology ². This form of pathology requires an appreciation of the effects of molecular changes on the pathobiology of the individual. In some countries, veterinary pathologists are almost extinct. Pathology training in veterinary medicine emphasizes exotic and domestic animals. Laboratory animal training is targeted to assist in board certification. While in high demand in industry, the majority of veterinary pathologists are reduced to mind-numbing, high throughput toxicological screening in the business environment. Pathology training in human medicine also emphasizes high-throughput diagnosis that merely demands pattern recognition, leaving little time for the appreciation of the natural history or molecular biology of disease. Very few medical training programs offer exposure to veterinary pathologists or to animal diseases. The same can be said of veterinary programs.

The development of genetic engineering in the mouse has created an opportunity to test molecular-based hypotheses on living mammals ². The study of these animals is critical to achieving progress in human medicine. Investigators now can control the mouse genome by targeting, inserting or deleting specific genes, and even controlling the temporal expression of genes. As a result, the mouse has become the surrogate for human disease. The optimism of current knock-out projects is based on these genetically manipulated mice. The proposed programs offer to knock-out the entire mouse genome, ultimately creating between 10,000 and 200,000 new strains of mice.

Therefore, genetic manipulation targeting rodents now enters the mix. Scientists can test their favorite molecule in the context of a living mammal. They can separate and isolate variables experimentally. They can study the natural history of the disease from origin to the ultimate consequence. Genomic biologists truly need the pathologists they previously ignored. Workforce studies in the United States and Europe have documented a shortage of qualified, experienced mouse pathologists ^1,2 (http://www.prime-eu.org/D02). The question is: Who is going to identify, classify and study the genome-based diseases in the new generations of mice ^1,2,4?

Our lack of preparation in pathology, unfortunately, has left the majority of North American and European research scientists without comparative pathologists who are qualified to examine the diseases in their molecularly-manipulated mice. This shortage has led to what has been, somewhat sarcastically, called “Do-it-Yourself” pathology ², performed by untrained and under-trained investigators with little access to widely dispersed and qualified pathologists. Do-it-Yourself pathology has led to the publication of a number of serious errors. Normal organs such as nipples and preputial glands have been described as neoplasms. Neuroendocrine tumors have been misdiagnosed as adenocarcinomas. Misuse of terminology by well-intended but inexperienced investigators has become another problem ^2,5,6. Unfortunately, the already lengthy list of published errors continues to grow.

As a result of the genomic revolution, we are entering an exciting period where comparative, Genomic Pathologists will be in great demand. Imagine the exciting opportunities when every slide examined reveals pathologic phenomena never previously observed. Examples from our own cases involve the recognition that different genes cause different and unique microscopic mammary tumor phenotypes in genetically engineered mice (GEM) ^7-9. These GEM tumors are unique and quite different from the spontaneous tumors observed in mammary tumor virus-infected mice. The identification of unique genotype-specific “signature” phenotypes was reinforced by the observation that tumors resulting from activations of whole pathways could share one or more phenotypic features. The concepts in mammary gland pathology are applicable to tumors in other organs ⁷. Some mice develop tumors that are exact histological phenocopies of human cancer. The unique genotype-related phenotypes observed in mice will soon be the basis for modern pathology. These genotype-phenotype correlations are the basis for Genomic Pathology.

What is the pathology of the future? The new pathology will require integration of evidence from diverse “-omic” sources with the natural history of disease and the microscopic changes. The various “-omics” are subheadings under the general heading of genomics ¹⁰. The next generation of pathologists will need to understand how genes and their products affect the disease processes. They will be the Genomic Pathologists.

However, experienced genomic pathologists are so widely dispersed that our medical and veterinary training programs lack faculty capable of teaching the subject matter. Without rapid identification and deployment of the available resources, the current scientific community will continue to be subject to serious errors. The pathological conditions of the numerous new mouse strains will continue to be misinterpreted and chaos shall reign.

How can the current generation of pathologists prepare itself and the next generation of pathologists? Modern dilemmas require modern solutions. We have proposed that those interested and qualified genomic pathologists join together in an International Academy of Genomic Pathology ^1,2. Such a group will become a society of like-minded people who will share experiences and teach each other the nuances of our discipline. The group can be geographically dispersed but remain connected through the modern marvel of communications, the internet. Existing technology permits whole slide imaging that can be placed on the Internet to be shared and annotated. Since whole slide images can be viewed at any magnification anywhere on the slide, they are like meeting with your friends, colleagues and students over a multi-headed microscope.

Further, the gathering of people with mutual interests represents an educational opportunity for the next generation. If we can meet and discuss cases, certainly our students can do likewise. The Academy of Genomic Pathology can become the faculty of an international university that teaches the principles of our discipline. We invite like-minded pathologists to join us in sharing experiences and opinions. We invite the yet unskilled to attend our courses to learn from the very best. It will be a great adventure.